The mediating role of depressive, anxiety, and physical symptoms on work ability index in employed women with breast cancer: a prospective study from Croatia

Aim To explore the relationship between the current work ability index (WAI) and depressive and anxiety symptoms in breast cancer (BC) patients and the role of depressive, anxiety, and physical symptoms in mediating this relationship. Methods This prospective study enrolled 83 employed women with BC. At baseline assessment (in the first three months following BC diagnosis) and follow-up assessment (one year after baseline), participants completed the WAI, Beck Depression Inventory-II, State-Trait Anxiety Inventory, and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire with a breast cancer-specific module. Mediation analyses were conducted to explore the mechanism by which depressive, anxiety, and physical symptoms influenced the relationship between WAI and depressive and anxiety symptoms. Results WAI was negatively associated with depressive and anxiety symptoms. The effect of baseline depressive and trait anxiety symptoms on WAI at follow-up was mediated by both depressive and trait anxiety symptoms, as well as by physical symptoms at follow-up. The effect of baseline state anxiety symptoms on WAI at follow-up was mediated only by state anxiety symptoms at follow-up. Conclusions Baseline depressive and anxiety symptoms affect WAI at follow-up not only through persisting depressive and anxiety symptoms observed at follow-up but also through physical symptoms at follow-up. This indicates that efforts aimed at improving psychological health may result in simultaneous improvements in both psychological and physical health, as well as the resulting WAI.

Breast cancer is the most diagnosed cancer worldwide, with 2 261 419 new cases in 2020 (1).The survival rate has significantly improved due to the impact of screening programs, improved diagnosis, and more effective treatments (2).However, it remains lower in developing regions, such as Croatia (2).Breast cancer patients are more likely to experience depression and anxiety compared with women with no prior cancer, which negatively affects disease management and health outcomes (3).Recent meta-analyses showed that the prevalence of depression and anxiety among breast cancer patients was up to 32.2% and 41.9%, respectively (4,5).
The increasing incidence of breast cancer patients among working-age women has highlighted the importance of workforce reintegration, making it a public health challenge (6).The work ability concept, introduced in 1981 (7), is defined as a balance between job demands, work environments, and an individual's physical and mental resources (8).Work ability is a strong predictor of return to work (9) and a critical factor for successful workplace reintegration in the cancer population (10,11).Work ability in breast cancer patients is lower upon diagnosis (12,13), and although it gradually improves over time (13)(14)(15), it remains lower years later (16,17) and compared with cancer-free controls (18,19).Work ability was previously mostly assessed with a single item from the Work Ability Index (WAI) questionnaire, the Work Ability Score (WAS).However, lower work ability among women was more frequently observed when using the WAI questionnaire than the WAS (20), suggesting that using the WAI questionnaire provides a holistic view of a participant's work ability, capturing nuances that a single item may miss.
Research on work ability among breast cancer patients has usually focused on clinical status, physical health, work environment, individual characteristics, and societal factors (21) rather than exploring depressive and anxiety symptoms (22), which have been found to be associated with work ability in the cancer population (23).Previous studies have mostly reported a negative association between depressive symptoms and work ability, whereas the association between anxiety symptoms and work ability was predominantly found to be non-significant (23).Nonetheless, there are studies that did not observe the association between depressive symptoms and work ability (8) and, conversely, studies that did observe the association between anxiety symptoms and work ability (22,24).As the issue has so far been addressed mostly through crosssectional surveys, it is important to provide longitu-dinal data to enhance understanding of the relationship between the WAI and depressive and anxiety symptoms in breast cancer patients.It is also important to understand whether this relationship is moderated by other factors, such as physical symptoms, which have been associated with a variety of work outcomes, including return to work, employment, and work ability (23)(24)(25).
To the best of our knowledge, no study so far has investigated the association between the WAI and depressive and anxiety symptoms in the cancer population using the WAI questionnaire, the Beck Depression Inventory-II (BDI-II), and the State-Trait Anxiety Inventory (STAI).The aim of this study was to examine the association between the WAI and depressive and anxiety symptoms and the possible role of depressive, anxiety, and physical symptoms in mediating the relationship between the WAI and depressive and anxiety symptoms in breast cancer patients.

Participants
The inclusion criteria for this With the power value set at 0.80 and the indirect effect in the mediation analysis tested with the percentile bootstrap confidence interval, the sample of 78 participants was sufficient to detect significant effects if both the a and b coefficients were of medium size or larger (26).

Methods
This prospective study was conducted at the Zagreb University Hospital Center.Data were collected in the first three months after breast cancer diagnosis (baseline) and one year after the baseline (follow-up).The interval between baseline and follow-up was one year (mean = 1.0; standard deviation = 0.07).Eligible participants were approached from May 2021 to May 2022 for the baseline assessment and were given written information about the study.Additionally, eligible participants were informed that they would be contacted for a follow-up, and the procedures for such follow-up interactions were clearly outlined.After fully informed consent was obtained from all individual participants included in the study, participants completed the following questionnaires at baseline: the WAI, BDI-II, STAI, and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 version 3 (QLQ-C30) with the breast cancer-specific module (QLQ-BR23).Demographic, socioeconomic, and clinical data were also collected.For participants who participated at baseline, the same questionnaires were sent via post 12 months later.A pre-stamped, addressed envelope was included for ease of return.Participants not returning the survey within a month received reminder telephone calls and were considered lost to follow-up after three unreturned calls.This study was conducted in line with the principles of the Declaration of Helsinki.It was approved by the Ethics Committee of the University Hospital Centre Zagreb and the School of Medicine, University of Zagreb.

Measures
Demographic and socioeconomic data were collected using a self-reported questionnaire designed for this study.
The questionnaire gathered information about age, marital status, parenthood, household status, educational level, employment status, and monthly household income.Clinical data on the stage of breast cancer and therapy were obtained from the medical records.
Anxiety symptoms were assessed with the STAI (28), a 40item self-evaluation questionnaire that includes measures of state and trait anxiety.The State-Anxiety Scale (STAI-S) consists of twenty statements that evaluate the respondents' current anxiety levels, while the Trait-Anxiety Scale (STAI-T) consists of twenty statements that assess general anxiety feelings.A four-point rating indicates high-level anxiety, while one indicates absence.The scale ranges from 20 to 80, with a score of 40 or higher indicating clinically meaningful anxiety (28).
Physical symptoms were assessed with a composite measure of physical symptoms (the Physical Symptoms Measure, PSM).Although participants completed the entire QLQ-C30 and the QLQ-BR23, our analysis focused solely on the derived PSM to assess symptom severity.The PSM was derived from six symptom scales (fatigue, nausea and vomiting, pain, systemic therapy side effects, breast symptoms, and arm symptoms) and five single items related to various physical symptoms (dyspnea, insomnia, appetite loss, constipation, and diarrhea) from the QLQ-C30 and QLQ-BR23 (29).The score on the PSM is an average of the scores on these eleven scales or single items, ranging from 0 to 100, with a score of 0 indicating no physical symptoms and a score of 100 indicating the presence of all the assessed symptoms (30).

Statistical analysis
Descriptive statistics were used to summarize all variables: frequencies for categorical variables, and mean, standard deviation, median, and interquartile range for continuous variables.The normality of distribution for continuous variables was tested with the Shapiro-Wilk test, along with measures of skewness and kurtosis.The reliability of the BDI-II, STAI, and WAI questionnaires was assessed with test-retest correlations and Cronbach's alpha. www.cmj.hrwww.cmj.hr The correlation between depressive, anxiety, and physical symptoms and WAI was evaluated with Pearson correlation coefficient.The statistical significance level was set at P ≤ 0.05.To investigate the possible mediating role of depressive, anxiety, and physical symptoms in the relationship between depressive and anxiety symptoms at baseline and WAI at follow-up, three mediation analyses were conducted using a parallel multiple mediator model (Figure 1) (32).This approach was chosen as it allows the simultaneous assessment of two mediators.All three analyses included the following five covariates measured at baseline: age, education, marital status, household income, and therapy.All regression coefficients (β) were standardized.The significance of indirect effects was evaluated using 95% percentile bootstrap confidence intervals based on 5000 bootstrap samples.Statistical analyses were conducted with IBM SPSS version 25.0 (33).Mediation analyses were performed with the PROCESS macro version 3.5 (32).

RESuLTS
Baseline characteristics of participants are presented in Table 1.The reliability of the BDI-II and the STAI was satisfactory.Cronbach's alpha values for the BDI-II at baseline and follow-up were 0.89 and 0.91, respectively; for the STAI-T -0.92 and 0.93, respectively; and for both measurements of the STAI-S -0.95 (Table 2).Cronbach's alpha was not calculated for the WAI questionnaire due to the heterogeneity of its item scales, which deviate from the tau-equivalent model.Similarly, reliability indicators were not calculated for the PSM because it is not a measure of a single latent dimension.

DISCuSSION
Employing a combination of assessment tools, including the WAI questionnaire, BDI-II, and STAI, this prospective study explored the relationship between the WAI and depressive and anxiety symptoms in breast cancer patients in Croatia.This contribution to the literature provides a deeper understanding of the observed relationship, given that research on work ability in breast cancer patients in Eastern Europe is limited compared with findings from Western countries.By focusing on a Croatian cohort, this study addresses this research gap.
Within the first year after diagnosis, patients in this study had a moderate WAI score, which aligns with previous research (8,(13)(14)(15) and a low level of physical symptoms, which may be explained by the significant presence (94%) of early-stage cancer (IA and IIA) in our sample (Table 1).Additionally, the observed mean scores for depressive and anxiety symptoms closely matched the pooled mean scores for anxiety and depression among breast cancer patients measured by the STAI and BDI in recent meta-analyses (4,5).
Our research corroborates prior studies that found a negative association between WAI and depressive symptoms (23,34,35).However, it diverges from previous findings (23) as we observed a negative association between WAI and anxiety symptoms.Additionally, our research revealed a (  *Abbreviations: β -standardized regression coefficient; CI -confidence interval; BootLL -lower limit; BootuL -upper limit; a1b1 -specific indirect effect through mediator 1; a2b2 -specific indirect effect through mediator 2; c' -direct effect of the predictor on the outcome; a1, a2, b1, b2 -regression coefficients defining indirect effects of mediators 1 and 2. †The indirect effect was significant at P < 0.05 if zero was not included in the 95% confidence interval for that indirect effect.‡Variable measured at baseline.§Variable measured at follow-up.Croat Med J. 2024;65:101-10 www.cmj.hrpositive association between physical symptoms and depressive and anxiety symptoms, which aligns with the literature that highlights the prevalence of this symptom cluster and the necessity for an integrated care approach (36,37).We also found that higher levels of physical symptoms were associated with a lower WAI, which supports the conclusions from earlier studies (12,24,34,35).Cancer patients with a lower symptom burden and higher work ability are more likely to continue working after diagnosis and treatment (38).
Mediation analysis revealed that higher baseline depressive or trait anxiety symptoms were associated with lower WAI at follow-up, mediated by both depressive or trait anxiety and physical symptoms at follow-up.Existing literature strongly suggests that emotional functioning is associated with physical health (40,41).An important question is whether physical symptoms are related to emotions such as anxiety or depression or to emotion regulation.As a construct, emotion includes feeling, motor expression, and physiological activation.The physiological response to an emotion depends on the regulation strategy employed, whether adaptive or maladaptive (41,42).Adaptive emotion regulation strategies are positively associated with physical health (43,44) and with a decrease in depression and anxiety (45,46).Conversely, maladaptive emotion regulation strategies are associated with a decline in physical health (43,44) and a long-term increase in anxiety and depression (45,46).A recent review has emphasized the importance of emotion regulation in breast cancer management (47).Breast cancer patients using less adaptive emotion regulation strategies have more depressive and anxiety symptoms (48).Furthermore, emotion dysregulation may exacerbate physical symptoms in breast cancer patients (49).Therefore, it is possible that emotions may "contribute" to an increase in physical symptoms only when a maladaptive emotion regulation strategy is used.Our findings indicated that only state anxiety at follow-up mediated the relationship between baseline state anxiety and WAI at follow-up, in contrast to the mediation analyses involving trait anxiety and depressive symptoms, where physical symptoms at follow-up also acted as mediators.This distinction may be attributed to the nature of state anxiety's impact on physical functioning being potentially less intense and more transient compared with that of trait anxiety symptoms, despite the general expectation that all emotions affect physical functioning (41).
The study has several limitations, including the potential sampling bias due to the convenience sample used, which may lead to an incorrect population mean estimation.The response rate was 63%, with a 25% dropout rate after one year, resulting in selection bias.The study focused on employed breast cancer patients, which raises questions about its generalizability to non-working patients.Additionally, the study did not assess depressive, anxiety, or physical symptoms pre-diagnosis, and no measures of emotion regulation were applied.Finally, we considered only two time points; however, it could be useful to monitor the association between WAI and depressive and anxiety symptoms over time to provide a more nuanced understanding of the relationship observed.
In conclusion, our findings indicate that baseline depressive and anxiety symptoms impact WAI at follow-up, not only through depressive and anxiety symptoms but also through physical symptoms at follow-up.This strengthens our understanding of the complex relationship between depressive, anxiety, and physical symptoms and WAI, all of which have been identified as factors in work-related studies in breast cancer populations.Research emphasizes the importance of routine mental health screening after diagnosis, as impaired WAI may be concealed by unrecognized baseline depressive and anxiety symptoms that worsen over time.Furthermore, tailoring targeted interventions and timely identification of treatment-related symptoms can provide comprehensive care that considers both mental and physical aspects, significantly impacting the WAI of breast cancer patients.
Funding None.
Declaration of authorship IPB, BK, DM conceived and designed the study; RV, KK acquired the data; IAK, MB, TPB analyzed and interpreted the data; IPB IAK, MB, TPB, RV, KK drafted the manuscript; BK, DM critically reviewed the manuscript for important intellectual content; all authors gave approval of the version to be submitted; all authors agree to be accountable for all aspects of the work.
Competing interests All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.

FIguRE 1 .
FIguRE 1. (A) Mediation model with work ability index (Y) at follow-up as the outcome, depressive symptoms (X) at baseline as the predictor, and depressive symptoms (M1) and physical symptoms (M2) at follow-up as the mediators.(B) Mediation model with work ability index (Y) at follow-up as the outcome, trait anxiety (X) at baseline as the predictor, and trait anxiety (M1) and physical symptoms (M2) at follow-up as the mediators.(C) Mediation model with work ability index (Y) at follow-up as the outcome, state anxiety (X) at baseline as the predictor, and state anxiety (M1) and physical symptoms (M2) at follow-up as the mediators.*Abbreviations: X -predictor; Y -outcome; M1 -mediator 1; M2 -mediator 2; a1, a2, b1, b2 -regression coefficients defining indirect effects of mediators 1 and 2; c' -direct effect of the predictor at baseline on the outcome at follow-up.
5 ± 12.72 at baseline, and 41.0 ± 9.85 and 41.1 ± 11.46 at follow-up, respectively (Table2).Clinically significant symptoms of depression, trait anxiety, and state anx- iety were observed in 17%, 49%, and 51% of participants at baseline, respectively, and in 22%, 52%, and 52% at followup.The PSM score indicated that breast cancer patients experienced a low level of physical symptoms, with a mean score of 19.8 ± 14.04 at baseline and a median score of 17.7 (IQR 16.1) at follow-up (Table2).

TABLE 1
*Data are presented as n (%) or mean ± standard deviation.†Monthlyhousehold income in euros (€).‡Based on the TNM Classification of Malignant Tumours.

TABLE 2 .
Descriptive statistics, measures of distribution normality and reliability (N = 83)* *Abbreviations: M -mean; sd -standard deviation; Md -median; IQR -interquartile range; min -minimum sample result; max -maximum sample result; α -Cronbach's alpha; test-retest r -Pearson correlation between baseline and follow-up; SW -Shapiro Wilk test statistic value; SW p -Shapiro-Wilk test significance level; BDI-II -Beck Depression Inventory-II; STAI-T -trait subscale of the State-Trait Anxiety Inventory; STAI-S -state subscale of the State-Trait Anxiety Inventory; WAI -Work Ability Index questionnaire; PSM -Physical Symptoms Measure.†Variable measured at baseline.‡Variable measured at follow-up.§Results of test-retest r are significant at P < 0.01.www.cmj.hr

TABLE 3 .
Intercorrelations between work ability index, depressive symptoms, trait anxiety, state anxiety, physical symptoms, income at baseline and at follow-up, and age at baseline (N = 83)*

TABLE 4 .
Standardized regression coefficients for the specific indirect effect through mediator 1, specific indirect effect through mediator 2, and the direct effect of the predictor on the outcome work ability index at follow-up for three mediation analyses (N = 83)*